There have been known a variety of carbapenem compounds, some of those compounds have been put on practical use and commercially available. For example, in JPA S60(1985)-233076, there is disclosed (1R,5S,6S)-2-[(3S,5S)-5-dimethylaminocarbonylpyrrolidin-3-ylthio]-6-[((R)- 1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid, i.e. Meropenem.
And, in EP-A-289801, there is disclosed (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a]pyrazolium-6-yl)thio]-6-[(R)- 1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate, i.e. Biapenem.
These compounds are regarded to improve the stability to renal dehydropeptitase (DHP-I) which is considered as a drawback of conventional carbapenem compounds, thus these compounds have now come to be administered singly without combination with an enzyme inhibitor.
On the other hand, on carbapenem substituted with 2-(N-containing aromatic heterocyclic ring) ethylthio group at 2-position, there are several reports.
For example, in AU-A-8319342, there is disclosed compounds represented by the formula ##STR2##
wherein R.sup.1 stands for, e.g. H, R.sup.8 stands for, e.g. H, R.sup.15 stands for, e.g. H, R.sup.2' stands for a conventional carboxyl-protecting group which is readily removable, A stands for C.sub.1-6 straight-chain or branched alkylene, and ##STR3##
stands for mono-, bi or polycyclic aromatic heterocyclic group, and the ring is linked with A through carbon atom constituting the ring, or their salts. As specific examples, however, only the following three compounds are disclosed, ##STR4##
and, these compounds are described only as intermediates for synthesizing a carbapenem compound having, at 2-position of the carbapenem skeleton, a monocyclic or polycyclic N-containing aromatic heterocyclic alkylthio group quaternarized by N-alkylation, but no use of these compounds as antibacterial agents is disclosed.
And, while, in EP-A-170073 and EP-A-242134, there are disclosed compounds having formulae: ##STR5##
having N-containing aromatic heterocyclic alkylthio group at 2-position of the carbapenem skeleton, these compounds are described only as synthetic intermediates, and no use as antibacterial agents is disclosed at all. And, no specific examples of carbapenem compounds, whose 2-position is substituted with 2-(non-quaternary nitrogen-containing aromatic heterocycle) ethylthio group, are disclosed.
And, in JPA S63(1988)-63680, a (1R)-1-methyl carbapenem compound of the formula: ##STR6##
having, at 2-position of the carbapenem skeleton, aromatic ring alkylthio group, or alicyclic or aromatic heterocyclic alkylthio group is described. However, as specific example of the compound having, at its 2-position, an aromatic heterocyclic alkylthio group, disclosed in the above-mentioned official gazette, only a carbapenem compound having 2-(1H-imidazol-1-yl)ethylthio group is given, and the ethylthio group of this compound has the linkage through nitrogen atom on the aromatic heterocyclic ring.
Further, in AU 9336488, a (1R)-1-methyl carbapenem compounds of the formula: ##STR7##
wherein R is hydrogen, anion charge or an ester residue, and ##STR8##
wherein X, Y is the same or different, N or --CH.dbd., one of the portion of dotted line is a single bond and the other portion of dotted line is a double bond, is a bicyclic heterocyclic ring, is described. However, this reference does not show the compound having at 2-position of carbapenem skelton, a bicyclic heterocyclic ring-ethylthio group.
Carbapenem compounds now commercially available are poor in absorbability from digestive canal, which are used only as injectable preparations and are not put on practical use as orally administrable preparations.
Circumstances being such as above, clinically useful carbapenem compounds having, besides a broad antibacterial spectrum, strong antibacterial activities and stability to DHP-I, good oral absorbability have been ardently desired.